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U t e ro t o n i c M e d i c a t i o n s

Oxytocin, Methylergonovine,
Carboprost, Misoprostol

Cristianna Vallera, MD*, Lynn O. Choi, MD,


Catherine M. Cha, MD, Richard W. Hong, MD

KEYWORDS
 Oxytocin  Methylergonovine  Carboprost  Misoprostol  Uterine atony
 Uterotonic agent  Postpartum hemorrhage

KEY POINTS
 Uterotonic agents are widely used in the prevention and treatment of postpartum hemor-
rhage, and although oxytocin remains the first-line agent, a standardized guideline for
optimal dose and rate of administration has not been clearly defined.
 Methylergonovine is a highly effective second-line agent; however, it is associated with
severe vasoconstriction and is contraindicated for hypertensive patients.
 Carboprost is useful for escalation of treatment when oxytocin and uterine massage have
been insufficient to restore uterine tone, especially when methylergonovine is contraindi-
cated, but it can cause severe bronchospasm and is thus contraindicated in patients with
asthma.
 Misoprostol is characterized by low cost, stability in storage, broad availability, minimal
side effects, ease of administration, and multiple medical uses; however, recent studies
have called into question its effectiveness as an adjunct uterotonic agent, limiting its
role to scenarios in which other, injectable uterotonics are not readily available or easily
administered.

OXYTOCIN
Introduction
Oxytocin, the first-line agent in the prevention and treatment of postpartum hemor-
rhage, is a polypeptide structure that is produced in the paraventricular nucleus of
the hypothalamus and released by the posterior pituitary gland. It was first discovered
by Sir Henry Dale in 1909 when he discovered that a hormone from the pituitary gland

Disclosure Statement: The authors have nothing to disclose.


Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine
at UCLA, 757 Westwood Plaza, Suite 3325, Los Angeles, CA 90095-7403, USA
* Corresponding author.
E-mail address: cvallera@mednet.ucla.edu

Anesthesiology Clin - (2017) -–-


http://dx.doi.org/10.1016/j.anclin.2017.01.007 anesthesiology.theclinics.com
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2 Vallera et al

caused uterine contractions in a pregnant cat.1 It was the first polypeptide hormone
synthesized in 1953 by the American biochemist, Vincent Du Vigneaud.2 Oxytocin re-
mains the first-line agent in the management and prevention of uterine atony after
vaginal and operative delivery. The clinical roles of oxytocin in the obstetric population
include induction and augmentation of labor, and prevention and treatment of post-
partum uterine atony.

Structure/Activity
Oxytocin is a short polypeptide consisting of 9 peptides (nonapeptide). Its chemical
structure is C46H66N12O12S2, which is structurally similar to vasopressin, and both
are secreted by the posterior pituitary gland. A disulfide bridge connects 2 cystines
in the primary sequence (Cys1 and Cys 6), forming a ring.3
Oxytocin exerts a stimulatory effect on myometrial contractility by increasing the
intracellular concentration of calcium. This process is achieved by the release of cal-
cium in the sarcoplasmic reticulum and by enhanced entry of extracellular calcium.
Oxytocin binds to a G-protein on the surface of the uterine myocyte, resulting in the
generation of diacylglycerol (DAG) and inositol triphosphate (IP3) via phospholipase
C on phosphatidyl-inositol bisphosphate.4 DAG stimulates prostaglandin synthesis,
which also contributes to uterine contractions. IP3 stimulates the release of calcium
from the sarcoplasmic reticulum and increases the concentration of cytoplasmic cal-
cium.5 For sufficient activation of myometrial contraction, this increase in intracellular
calcium from the sarcoplasmic reticulum alone is not sufficient and entry of extracel-
lular calcium is required. This process is mediated by the oxytocin–G-protein complex,
which causes a conformational change in voltage-gated calcium channels allowing
the influx of extracellular calcium. Calcium then binds to calmodulin and activates
myosin light-chain kinase, which is the fundamental contraction mechanism of uterine
smooth muscle.6
The rate-limiting step for the action of oxytocin is the concentration of oxytocin re-
ceptors on the myometrium. Of note, the oxytocin receptor is absent in a nonpregnant
uterus. Once a woman becomes pregnant, oxytocin receptors appear in myometrial
cells at approximately 13 weeks’ gestation and increase in concentration until term.
The distribution of oxytocin receptors in the uterus is not uniform throughout. There
is a higher concentration of receptors in the fundus of the uterus, and the concentra-
tion decreases closer to the lower uterine segment and cervix.5 This uneven receptor
distribution may explain the less prominent uterine contraction seen in the lower third
of the uterus after administration of oxytocin.

Pharmacokinetics
Oxytocin is absorbed via intravenous, intramuscular, buccal, or nasal mucosal routes,
but it is most commonly administered intravenously to allow for precise dosing and
rapid discontinuation if adverse reactions occur. Intravenous injection has an immedi-
ate onset of action compared with intramuscular injection, which takes approximately
3 to 7 minutes.7 The recommended dose for intramuscular injection during cesarean
delivery is 10 units after delivery of the placenta. Once absorbed, oxytocin redistrib-
utes to the extracellular space and does not bind to plasma proteins. The half-life of
oxytocin is 10 to 12 minutes. There is a linear increase in plasma concentration of
oxytocin after a continuous infusion. It takes approximately 20 to 30 minutes to reach
a steady-state in plasma,8 and a maximum concentration is reached in approximately
40 minutes.9
Although the mechanism of oxytocin degradation is not clearly elucidated, there are
2 proposed pathways that contribute to oxytocin metabolism, which involve cysteine

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Uterotonic Medications 3

aminopeptidase and postproline endopeptidase. Aminopeptidase splits the ring


structure of oxytocin by cleaving tyrosine and destroys the conformational active
state. Postproline endopeptidase cleaves oxytocin between proline and leucine, split-
ting the molecule into 2 inactive moieties. There are other minor enzymes involved in
inactivating oxytocin, which include carboxypeptidase and leucine aminopeptidase.10

Clinical Role
Uterine atony is the most common cause of severe postpartum hemorrhage. Conse-
quently, the use of uterotonic agents is crucial to reducing the risk of postpartum hem-
orrhage and improving maternal safety. Oxytocin is the drug of choice for prevention
and treatment of uterine atony after vaginal and operative deliveries. It is also widely
used to induce and augment the labor process.

Routes and Dosages


The dosage and method of administration of oxytocin for prevention and treatment of
uterine atony vary considerably and remain controversial. The recommended routes
for administration are intravenous or intramuscular. A Cochrane review comparing
the administration of prophylactic oxytocin for postpartum hemorrhage found no dif-
ference in efficacy or side effects when comparing intravenous and intramuscular
administration.7 Potentially detrimental cardiovascular side effects are related to the
dose and rate of administration. Rapid intravenous bolus injections of up to 3 to 5 units
have resulted in cardiovascular collapse and even death.11 In a study by Carvalho and
colleagues,12 the ED90 for nonlaboring patients undergoing elective cesarean delivery
was found to be 0.35 units. Balki and colleagues13 studied laboring women who
required cesarean delivery for labor arrest that had been induced or augmented
with oxytocin for approximately 10 hours and found that the ED90 was 2.99 units. Balki
and his colleagues13 demonstrated that the requirement for oxytocin in patients who
were already exposed to oxytocin had about 9 times the requirement of nonlaboring
patients.
There are several concepts that contribute to the different dosage requirements in
laboring versus nonlaboring patients. Oxytocin receptor expression and density in
the myometrium increases progressively throughout pregnancy and reaches a peak
at term.14 The change in receptor density explains why patients with term, elective ce-
sarean deliveries are more sensitive to low dosages of oxytocin.12
Labor and oxytocin exposure further changes oxytocin receptor distribution. Pha-
neuf and colleagues15 found that oxytocin receptor density was significantly lower
in patients who had been induced with oxytocin compared with those who had spon-
taneous onset of labor. Repeated exposure of the myometrial cells to oxytocin leads to
a significant loss in the capacity to respond to additional oxytocin, which is likely due
to oxytocin receptor desensitization. Repeated doses of oxytocin may become
increasingly ineffective and second-line uterotonics (ergometrine, prostaglandins
F2a and E1) should be considered earlier for laboring patients, especially in those
who have received oxytocin.
The recommended dose, timing, and rate of administration for oxytocin during ce-
sarean delivery remain ambiguous. A randomized, double-blind study by Kovecheva
and colleagues16 used a “Rule of Threes” algorithm to minimize the dose-related and
rate-related side effects of oxytocin by applying a standardized method of adminis-
tering oxytocin during elective cesarean deliveries. The algorithm starts with an initial
3 units of oxytocin given over 5 seconds after delivery of the fetus, and uterine tone is
assessed every 3 minutes thereafter. An additional 3 units of oxytocin is given if inad-
equate tone is observed after each 3-minute interval. If a third bolus of oxytocin is

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4 Vallera et al

given for inadequate tone and uterine atony continues, then a second-line uterotonic
agent is recommended. The “Rule of Threes” algorithm minimizes the total dose of
oxytocin administered and may represent an optimal regimen for elective cesarean
deliveries.
Side Effects and Contraindications
Oxytocin used for prophylaxis or treatment of postpartum hemorrhage during cesar-
ean delivery may result in several side effects. The adverse effects include hemody-
namic instability (hypotension, tachycardia, myocardial ischemia, and arrhythmias),
nausea, vomiting, headache, and flushing. The most common side effects are hypo-
tension and tachycardia and are related to the dose and rate of administration. Hypo-
tension is predominately caused by transient relaxation of vascular smooth muscle
cells via calcium-dependent stimulation of the nitric oxide pathway, which leads to pe-
ripheral vasodilation, hypotension, and a compensatory increase in heart rate, stroke
volume, and cardiac output.17 These cardiovascular effects may be well tolerated in a
healthy patient but caution must be taken when administering to patients with
abnormal ventricular function, valvular stenosis, or hypovolemia.4 Due to its structural
similarity to vasopressin, oxytocin administered in high dosages may lead to water
intoxication, hyponatremia, seizures, and coma.18
Summary
Oxytocin remains the first-line agent for prevention and treatment of postpartum hem-
orrhage after vaginal and cesarean delivery. Adverse side effects leading to cardiovas-
cular instability are dose and rate related. Currently, there are no standardized
administration guidelines for the administration of oxytocin, but a “Rule of Threes” al-
gorithm may be a safe method for oxytocin use during elective cesarean deliveries.
Although oxytocin has been used safely and effectively by obstetricians and anesthe-
siologists for many years, the benefits of oxytocin must be weighed against potentially
serious side effects.

METHYLERGONOVINE
Introduction
Methylergonovine has a long history of use for the treatment of postpartum hemor-
rhage due to uterine atony. It is a semisynthetic amide ergot derivative, which pro-
duces sustained contraction of the uterus without causing significant systemic
vasoconstriction in most cases.19 The American College of Obstetricians and Gyne-
cologists recommends methylergonovine as a second-line uterotonic for refractory
uterine atony.20 However, in 2012, the Food and Drug Administration (FDA) raised po-
tential safety concerns about methylergonovine-induced vasoconstriction causing
myocardial ischemia and infarction, which led to a revision of the methylergonovine
label.21
Structure/Activity
Ergot alkaloids were first isolated from ergot fungi and are derivatives of the tetracyclic
compound 6-methylergoline.19 Methylergonovine maleate (9,10-didehydro-N-[(S)-(1-
hydroxymethyl) propyl]-6-methylergoline-8beta-carboxamide maleate salt) is a
semisynthetic ergot alkaloid that is produced by a reaction of (1)-lysergic acid with
L-(1)-aminobutanol.22 Methylergonovine has low water solubility and is prepared as
a water-soluble maleate salt.23 Exposure to water or light leads to the formation of
6-hydroxy derivatives, which will be expedited in an acidic environment. It is easily
oxidized, and the oxidation produces a color change. Methylergonovine should be

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Uterotonic Medications 5

administered only if it is clear and colorless. When stored, methylergonovine should be


refrigerated. Stability is compromised when exposed to higher temperatures, light, or
humidity.19,22
Methylergonovine is a serotonergic receptor agonist in the smooth muscle. It is also
a weak antagonist of dopaminergic receptors and partial agonist of a-adrenergic re-
ceptors.22 Methylergonovine causes uterine contractions and relaxation at low doses,
but causes sustained contractions and increased basal tone at high doses.24 The
mechanism of action for uterine contraction is not well defined. Uterine contraction
is likely produced by methylergonovine agonist effects on the 5-HT2 receptor found
in uterine smooth muscle.22 Alternatively, methylergonovine could cause uterine
contraction through direct stimulation of the a-adrenergic receptors in the uterus,
which has been postulated to lead to calcium mobilization.25

Pharmacokinetics
The onset of action of intravenous methylergonovine is nearly immediate. After intra-
muscular injection, the onset is 2 to 5 minutes, and after oral administration the onset
is 5 to 10 minutes. If administered intravenously, methylergonovine is distributed from
plasma to peripheral tissue in 2 to 3 minutes. Peak plasma concentration following
intramuscular injection occurs in approximately 0.4 hour, and occurs approximately
1 hour after oral administration. Plasma levels have a biphasic decline with intramus-
cular absorption.21 The half-life of methylergonovine after intravenous administration
is 2.3 hours and after oral administration is 2.7 hours. The bioavailability is significantly
more variable with oral administration when compared with intravenous or intramus-
cular administration.22 Intramuscular injection had a greater bioavailability than oral
administration, likely due to first-pass metabolism by the liver. Ergot alkaloids are
mainly eliminated by hepatic metabolism.21

Clinical Role
Methylergonovine is used for the treatment postpartum hemorrhage due to uterine
atony or subinvolution. At high doses, it creates sustained contractions in the
uterus.23,24 The American College of Obstetricians and Gynecologists (ACOG)
recommends methylergonovine as a second-line uterotonic.20 When compared with
carboprost, methylergonovine has been associated with reduced risk of hemorrhage-
related morbidity in women with uterine atony refractory to oxytocin.26 Recently,
methylergonovine has also been used to treat migraines and cluster headaches and
to produce diagnostic coronary vasospasm in patients with variant angina.24,27

Route and Dosage


ACOG recommends methylergonovine at a dosage of 0.2 mg administered intramus-
cularly at a frequency of 2 to 4 hours as needed. ACOG also discusses some practi-
tioners’ preference to administer methylergonovine directly into the uterine corpus.20
However, it has been reported that inappropriate myometrial absorption of methyler-
gonovine was a suspected cause of myocardial ischemia, likely because the highly
vascularized myometrial tissue increased the rate of systemic uptake.28 Due to the po-
tential for hypertensive or cerebrovascular events, intravenous injection is not recom-
mended. If intravenous administration of methylergonovine is necessary as a
lifesaving measure, it should be given slowly over a period of more than 60 seconds
with close blood pressure monitoring. Methylergonovine also can be given orally for
up to 1 week.21

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Side Effects and Contraindications


The most common negative side effect of methylergonovine is hypertension due to
vasoconstriction. This can be associated with headaches or seizures.21 Methylergo-
novine has rarely been associated with coronary vasospasm, myocardial ischemia,
and myocardial infarction. Patients with coronary artery disease or risk factors for cor-
onary artery disease are at increased risk of developing acute coronary syndrome or
infarction. These risk factors include smoking, obesity, diabetes, and high cholesterol.
In a large retrospective study, no significant increase in myocardial ischemia or infarc-
tion was seen with methylergonovine administration. Of the patients with chronic
ischemic heart disease or risk factors for heart disease, only 1 case of myocardial
ischemia/infarction was found out of 14,489 patients who received methylergono-
vine.29 ACOG recommends avoiding methylergonovine in hypertensive patients.
Nausea and vomiting also have been reported. Other rare adverse reactions include
bradycardia, tachycardia, hypotension, dyspnea, thrombophlebitis, dizziness, and
diarrhea.21
Methylergonovine goes through CYP3A4 metabolism. Potent CYP3A4 inhibitors
(such as protease inhibitors, erythromycin, quinolones, ketoconazole) should be
avoided. Other ergot alkaloids or vasoconstrictors must be used with extreme caution
when coadministered. Other contraindications include sepsis, pregnancy, and
hypersensitivity.21

Summary and Discussion


Methylergonovine is recommended by ACOG and the Royal College of Obstetrics and
Gynecology as a second-line uterotonic. However, no recommendations are made
regarding the choice of a specific second-line agent. A recent study using a nation-
wide dataset found that the frequency of second-line uterotonics use was 7.1%.
Methylergonovine was used at a frequency of 5.2%, carboprost at 1.0%, and miso-
prostol at 1.2%.30 Methylergonovine has been shown to decrease the amount of post-
partum hemorrhage–related morbidity and reduced the amount to a greater extent
than carboprost.26 Although recent safety concerns about methylergonovine-
induced vasoconstriction causing myocardial ischemia and infarction have been
reported, the risk is exceedingly low. For a patient with no history or risk factors for
coronary disease, methylergonovine is an extremely effective agent to correct refrac-
tory uterine atony and mitigate the postpartum hemorrhage.

CARBOPROST
Introduction
Carboprost (US brand name Hemabate) is an analog of prostaglandin F2a. Maternal
concentrations of endogenous prostaglandins increase during labor, with peak con-
centrations occurring at the time of placental separation. This prostaglandin surge
likely contributes to uterine contractions and placental delivery. One cause of uterine
atony may be a deficiency of prostaglandin F2a concentration increase during the
third stage of labor.31,32

Structure/Activity
Rapid metabolism of naturally occurring prostaglandins limited their usefulness for
clinical application and led to the development of analogs with longer durations of ac-
tion. Carboprost tromethamine, the active ingredient in Hemabate, is an analog of
15-methyl prostaglandin F2a. Naturally occurring prostaglandins are oxidized at car-
bon 15, which causes rapid inactivation of primary prostaglandins. On the analog, this

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Uterotonic Medications 7

oxidation is completely blocked, with the hydrogen being replaced by a methyl


group.33
Myometrial intracellular free calcium concentration is increased by prostaglandins.
The increased availability of calcium leads to increased myosin light-chain kinase ac-
tivity, augmenting the contractile response of the uterus.34,35
Pharmacokinetics
Carboprost is injected intramuscularly for the treatment of postpartum hemorrhage.
Plasma levels peak 20 minutes after injection, and decline by approximately half after
2 hours.33
Urinary excretion is the major route of elimination of carboprost. Excretion of metab-
olites is almost complete 24 hours after subcutaneous administration in women.
Approximately 80% of the dose is excreted within the first 5 to 10 hours, with an addi-
tional 5% of the dose excreted over the next 20 hours. Three major metabolites of car-
boprost have been identified in human urine. Approximately 1% of the dose is
excreted as intact drug.36
Clinical Role
Carboprost is a second-line treatment for uterine atony. Most cases of uterine atony
respond to manual uterine massage and oxytocin. For refractory uterine atony with
or without postpartum hemorrhage, both methylergonovine and carboprost are
used in an effort to avoid surgical interventions such as ligation of the uterine or hypo-
gastric arteries or peripartum hysterectomy. Methylergonovine is associated with a
lowered risk of hemorrhage-related morbidity during cesarean delivery when
compared with carboprost. Women receiving carboprost were 1.7 times as likely to
have hemorrhage-related morbidity.26 Carboprost is a treatment alternative for pa-
tients with hypertensive disorders, such as preeclampsia (a relative contraindication
to methylergonovine), and for patients with atonic bleeding refractory to
methylergonovine.34,37
Routes and Dosage
Carboprost for uterine atony should be administered intramuscularly. The recommen-
ded dose is 250 mg. The dosage may be repeated every 15 to 30 minutes. Total dose
should not exceed 2 mg (8 dosages). In clinical trials, 80% of patients with uterine
atony responded to less than 250 mg and 95% of patients responded to less than
500 mg.36,38 For women with severe postpartum hemorrhage who had already failed
conventional therapy with intravenous oxytocin, intramuscular methylergonovine
and manual uterine massage, studies showed a rescue rate of 86% overall, with
88% of subjects responding after 2 intramuscular doses.34 The need for repeated
doses should be evaluated based on clinical effect.
Side Effects and Contraindications
Frequently reported side effects of carboprost administration include nausea, vomit-
ing, and diarrhea. The cause of these adverse effects is likely the stimulation of smooth
muscle in the gastrointestinal tract. Flushing, pyrexia, and myalgia are also reported.
Moderate increases in blood pressure are often seen, caused by vascular smooth
muscle contraction.36 The observed effect on blood pressure is clinically insignificant
when compared with the effect of methylergonovine.
Carboprost can precipitate bronchospasm, increased intrapulmonary shunt frac-
tion, abnormal ventilation-perfusion ratio, and hypoxemia. Patients with asthma are
particularly susceptible to these complications, but there are rare documented cases

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8 Vallera et al

of bronchospasm in patients without asthma.38–41 In asthmatic patients, the resulting


bronchospasm can be severe and can occur after only 1 dose.
The use of carboprost in breastfeeding mothers has not been specifically studied,
but based on plasma clearance rates, the manufacturer recommends that breastfeed-
ing be delayed for at least 6 hours after administration.36

Summary and Discussion


Carboprost, an analog of prostaglandin F2a, has an important role in the management
of refractory uterine atony. When first-line treatment with manual uterine massage and
oxytocin has failed, and methylergonovine is contraindicated or has not been effec-
tive, it is imperative that uterine tone be restored to prevent life-threatening post-
partum hemorrhage. Carboprost is successful in triggering uterine smooth muscle
contraction after the first or second dose in approximately 90% of cases. Although
the mechanism of action can lead to unpleasant side effects, such as vomiting or diar-
rhea, these issues are minor when compared with the risks associated with major
hemorrhage, massive transfusion, or surgical intervention. The only relative contrain-
dication to the use of carboprost is asthma. Asthmatic patients can experience life-
threatening bronchospasm after a single dose of carboprost.

MISOPROSTOL
Introduction
Misoprostol, a synthetic analog of prostaglandin E1, has a long history of medical
application. Naturally occurring prostaglandin E1 (PGE1) protects gastric mucosa
through reduction in gastric acid secretion and stimulation of mucus and bicarbonate
secretion. Originally developed as a treatment for peptic ulcers, misoprostol found a
vital role in obstetric and gynecologic patients thanks to its effects on uterine smooth
muscle and the cervix. The list of clinical applications has since grown to include medi-
cally induced abortion, medically assisted evacuation after miscarriage, cervical
ripening, induction of labor, and treatment of uterine atony.

Structure/Activity
Misoprostol is a synthetic prostaglandin E1 analog (15-deoxy-16-hydroxy-16-methyl
PGE1). Compared with PGE1, misoprostol exhibits superior performance across 3
notable areas. PGE1 is rapidly metabolized, which hinders its utility via oral and paren-
teral routes, and it also produces more side effects while being less chemically stable.
PGE1 has a carboxyl group at carbon 1 and a hydroxyl group at carbon 15. Misopros-
tol improves on the characteristics of PGE1 by having a methyl ester at carbon 1
(imparting greater duration of action), a carbon 16 methyl group, and hydroxyl group
at carbon 16 rather than carbon 15. The modifications at carbon 16 increase oral ac-
tivity, duration of action, and safety.42

Pharmacokinetics
Misoprostol has differing pharmacokinetic profiles depending on the route of admin-
istration, and clinically useful routes include the following: oral, buccal, sublingual,
vaginal, and rectal. In terms of speed of onset, the oral and sublingual routes appear
to be superior. Sublingual administration yields the highest peak plasma concentra-
tions of any route, and peak plasma concentrations are seen in approximately 30 mi-
nutes.43 Concomitant food intake and antacid use will measurably reduce the
availability of oral misoprostol, but it is not clear whether the effect is clinically
significant.44

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Uterotonic Medications 9

Vaginal administrations of misoprostol produce slower onset and a longer time to


peak effect than routes involving the mouth; however, the decline in plasma concen-
tration is also much slower, with corresponding superiority in terms of bioavailability.
Vaginal absorption can vary significantly with the vaginal environment, where pH
changes and varying amounts of vaginal discharge can potentially alter the observed
pharmacokinetics.45 In the context of vaginal bleeding from uterine atony or medical
abortion, vaginal absorption may be reduced.
Buccal misoprostol exhibits a time to peak concentration and a gradual fall in con-
centration comparable to the kinetics of vaginal misoprostol, but with inferior bioavail-
ability to both sublingual and vaginal routes.46,47
Rectal misoprostol generates the slowest onset, with a long offset time comparable
to that of vaginal misoprostol.48 Serum concentrations, reflecting bioavailability after
rectal administration, remain inferior to levels seen after vaginal misoprostol.46
Misoprostol exhibits extensive renal clearance, and renal impairment may extend its
half-life as well as increase bioavailability and maximum plasma concentrations. How-
ever, there is no recommended dose adjustment for patients in renal failure.44
Misoprostol acid is found in breast milk for several hours after oral administration,
albeit in concentrations lower than maternal serum concentrations.49,50 The FDA
warns that nursing mothers may cause significant diarrhea in their infants by breast-
feeding under these circumstances.44

Clinical Role
Misoprostol is a second-line agent for treatment of uterine atony. During and after the
third stage of labor, oxytocin is the first-line agent given to all patients to prevent post-
partum hemorrhage. In situations in which oxytocin is not immediately available, or
when oxytocin fails to produce a desired result, methylergonovine has advantages
of speed and efficacy over misoprostol. However, in patients with a contraindication
to methylergonovine therapy, or in environments in which skilled attendants and sup-
plies are not available to deliver injectable medications, or if methylergonovine is not
immediately available, misoprostol can be used.51 In medically underserved areas
where the supply and storage of expensive, or light-sensitive or temperature-
sensitive medications is limited, misoprostol tablets offer an inexpensive and easy-
to-store uterotonic option.52 Misoprostol also can be given to patients whose uterine
atony is refractory to earlier interventions,53 but in a major meta-analysis there was no
clear benefit to using misoprostol as an adjuvant to oxytocin in terms of major out-
comes, such as mortality and blood loss.54
In a meta-analysis of recent large randomized controlled trials involving misoprostol
versus placebo, misoprostol effectively prevented postpartum hemorrhage and se-
vere postpartum hemorrhage by 24% and 41%, respectively.55

Routes and Dosage


Numerous studies have evaluated the optimal route and dose for misoprostol in post-
partum hemorrhage applications. As a first-line treatment in situations in which active
management of the third stage of labor is not possible, 800 mg has the most evidence
supporting its safety and efficacy as a single sublingual dose.54 For postpartum hem-
orrhage, 600 mg has been advocated as an oral or sublingual treatment dose53 and this
is also a well-studied prophylactic dose.55 A 600-mg oral dose of misoprostol begins to
act within 3 to 5 minutes.51 However, oral doses of 400 to 600 mg do not appear to
have differing clinical efficacy, whereas the larger dose is associated with a greater
incidence of pyrexia.56,57 Repeat doses of misoprostol are not recommended for at
least 2 hours, or 6 hours in patients exhibiting shivering and pyrexia.53

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Vaginal administration of misoprostol may not be practical during active postpartum


hemorrhage with vaginal bleeding. Rectal administration has been studied, but that
route is not recommended for treatment or prevention of atonic uterine bleeding.
Side Effects and Contraindications
Misoprostol has no serious side effects in doses and durations of therapy that are clin-
ically appropriate for the treatment of uterine atony. If misoprostol is effective in elicit-
ing uterine contractions, patients may complain of cramping. Gastrointestinal upset
may occur. With increasing doses, misoprostol has been described to cause shivering
and corresponding hyperthermia.58 Side effects are self-limited and may be more
common with sublingual misoprostol administration due to its pharmacokinetics,
notably the high peak serum concentrations that correspond to that route.47
The toxic dose of misoprostol is not known. A dose of 1600 mg in a single day has
been tolerated in patients but may cause gastrointestinal upset. Overdose may pro-
duce symptoms including sedation, tremor, convulsions, dyspnea, abdominal pain,
diarrhea, fever, palpitations, hypotension, or bradycardia. Treatment for overdose is
supportive, as there is no known reversal agent and dialysis is unlikely to help clear
misoprostol acid, the detectable and biologically active form of misoprostol.44
There are no contraindications to using misoprostol in postpartum patients other
than history of an allergic reaction.53 The only FDA warning related to misoprostol ap-
plies to pregnant or potentially pregnant women due to its abortifacient and possible
teratogenic effects.44
Summary and Discussion
Misoprostol has a role in the management of uterine atony. Because of its wide variety
of clinical applications, misoprostol is an active topic of research. Questions remain
about the optimal dose and route, and whether prophylactic use should be limited
to situations in which active management of the third stage of labor (eg, oxytocin) is
not possible. But its ease of administration, modest side-effect profile, lack of contra-
indications, and proven efficacy make it a useful option.

SUMMARY

Conditions that increase the risk of uterine atony, such as overdistention of the uterus
(as seen with multiple gestations and polyhydramnios), magnesium sulfate administra-
tions and chorioamnionitis are frequently encountered in clinical practice. With the
incidence of postpartum hemorrhage increasing and with uterine atony a contributor
in many cases, it is important to understand the risks and benefits of commonly used
uterotonic agents.59 Manual uterine massage and oxytocin are almost universally
accepted as the first-line treatments of choice for uterine atony. When this combina-
tion is ineffective, it is often appropriate to administer a second-line uterotonic agent.
Methylergonovine and carboprost are second-line agents in most treatment proto-
cols. The choice of which therapeutic agent to use should be based on the comorbid-
ities of the patient and the clinical judgment of the practitioners involved in the case.
Misoprostol remains a treatment option for uterine atony, but its utility as an adjunct to
the other uterotonic medications may be limited.

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